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The Diels-Alder Reaction James Partridge August 27 th , 2010 1

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The Diels-Alder Reaction

James Partridge August 27th, 2010

1

Easy Question

+

2

Diels-Alder Reaction

Otto Diels 1876-1952 Kurt Alder 1902-1958

3

Diels-Alder Reaction

•  Identified products of quinnone and cyclopentadiene reaction.

•  Paper-1928 •  Nobel prize 1950

O

O

+

O

O

H

H

O

O

H

H

H

H

4

O. Diels, K. Alder, Justus Liebigs Ann. Chem. 1928, 460, 98 ± 122

Diels Alder quotes •  “Thus it appears to us that the possibility of synthesis

of complex compounds related to or identical with natural products such as terpenes, sesquiterpenes, perhaps even alkaloids, has been moved to the near prospect.”

•  “We explicitly reserve for ourselves the application of the reaction developed by us to the solution of such problems.”

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What is the Diels Alder Reaction?

•  Thermal π4s +π2s cycloadition reaction •  Concerted and stereospecific •  200°, 17h, 90 ATM, 18%

6

+

DIene Dieneophile 6 memebered ring

L.M. Joshel, L.W.Butz, J. Am. Chem. Soc., 63,3350, (1941)

What Makes Diels Alder reactions work?

•  Frontier Orbital theory

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DIeneophile DIene

HOMO

LUMOLUMO

HOMO

ΔE

The Endo rule

•  Ewoks, small race of primative mamals, live only on the forest moon of Endor

•  ………Wait, that the Endor rule

8

The REAL endo rule •  Provide answers, explain stereochemistry

9

MeO

CO2Me

CO2Me

MeO+

+

O

MeO

MeO

CO2Me

CO2Me

Diastereospecific!

O

H

H

O

main product

(+/-)

The REAL endo rule

•  Secondary orbital overlap accounts for endo selectivity

•  Will be converted thermally to exo

•  If no 2ndary orbital overlap, exo ts is dominant

10

O

Lots of cycloaddition •  Hint: 2+2+2, then retro 2+2, then 4+2

R. L. Funk, K. P. C. Vollhardt, J. Am. Chem. Soc. 1979, 100, 215- 217;

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OMe TMSTMSCpCo(CO)2

136°C, 41 h[2+2+2]

decane174°C 20h

71%

TMS

TMS

Me O

H H

H

HO

Me

H H

H

Estrone

intermediate

TMS

TMS

O

Me

TMS

TMS

Me O

Retro Diels Alder

12

P. A. Jacobi, C. A. Blum, R. W. DeSimone, U. E. S. Udodong, Tetrahedron Lett. 1989, 30, 7173 - 7176.

N O

Me OMe

NH+TBSO

O

TMS

O

OMe

TMS

ON

H

TBSO

O

N

H

O

H

(-) norsecurinine

50% overall

Michael NO

Me

OMe

N

OTBS

O

TMS

DA

NO

Me OMe

TMS

ON

H

OTBS

Retro Diels Alder-MeCN

NO

Me OMe

TMS

ON

H

OTBS

Review from last week

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N

OPG

CO2Me

Br

NBocO

OPG

SnBu3Pd(PPh3)4

toluene110°C, 30h N

O NBoc

OPG

CO2MeH

OPG68%

NH

N

N

N

OH

H

H

H

manzamine A

RXNName, product,

N

OPG

NBocO

OPG

MeO2C

S. F. Martin, J. M. Humphrey, A. Ali, M. C. Hillier, J. Am. Chem. Soc. 1999, 121, 866 ± 867

Boger Diels-Alder

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D. L. Boger, S. Ichikawa, H. Jiang, J. Am. Chem. Soc. 2000, 122, 12 169 - 12 173.

O

O

N

MeOMeO

nPrMe

O

OMeMe O

O

NMeO

MeO

nPr Me

OMeMe

H

H

H

HO

97%100% EXO

N MenPr

O O

OHHO

rubrolone aglyconO

OO

OMeMe

Boger puts off gas

D. L. Boger, C. M. Baldino, J. Am. Chem. Soc. 1993, 115, 11418-11425 ; H. H. Wasserman, R. W. DeSimone, D. L. Boger, C. M. Baldino, J.

Am. Chem. Soc. 1993, 115, 8457-8458.

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OMe

OMeMeO

MeO

+ NN N

N

CO2Me

CO2Me

60°C

CHCl35 Days

NN

NNR

R

MeOR

ROMe

N

N Me

Me

CO2HCO2H

MeO

MeO

CO2Me

MeO2C

2 eq

NN

NN

NN

NNR

ROMeOMe

MeOMeO

R

R

R=CO2Me

-2N2

NN

NNR

ROMeOMe

MeOMeO

R

R

-2MeOH65%

O2, Rose Bengal, hν

colidine:H2O: iPrOH2:6:1

O

O

Cl Cl

Cl

Cl

O

I

I IOH

I

HO

Rose Bengal

OO

NOON

MeO2C

OOH

O

OH

MeO2CMeO

OMe

Boger puts off MORE gas

16

OO

NOON

MeO2C

OOH

O

OH

MeO2CMeO

OMe

N

N

OO

MeO2C

HO CO2Me

HOMeO

MeO

isochrysohermidin